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Molecular Insights into Human Monoamine Oxidase B Inhibition by the Glitazone Antidiabetes Drugs

2011; American Chemical Society; Volume: 3; Issue: 1 Linguagem: Inglês

10.1021/ml200196p

1948-5875

Claudia Binda, Milagros Aldeco, Werner J. Geldenhuys, Marcello Tortorici, Andrea Mattevi, Dale E. Edmondson,

Adenosine and Purinergic Signaling

The widely employed anti-diabetic drug pioglitazone (Actos) is shown to be a specific and reversible inhibitor of human monoamine oxidase B (MAO B). The crystal structure of the enzyme-inhibitor complex shows the R-enantiomer is bound with the thiazolidinedione ring near the flavin. The molecule occupies both substrate and entrance cavities of the active site establishing non-covalent interactions with the surrounding amino acids. These binding properties differentiate pioglitazone from the clinically used MAO inhibitors, which act through covalent inhibition mechanisms and do not exhibit a high degree of MAO A versus B selectivity. Rosiglitazone (Avandia) and troglitazone, other members of the glitazone class, are less selective in that they are weaker inhibitors of both MAO A and MAO B These results suggest that pioglitazone may have utility as a "re-purposed" neuro-protectant drug in retarding the progression of disease in Parkinson's patients. They also provide new insights for the development of reversible isoenzyme-specific MAO inhibitors.